Dihydronepetalactone (“DHN”) is a useful chemical that has been shown to have a variety of properties such as insect repellency [see, for example, Jefson et al (J. Chemical Ecology [1983] 9:159-180), or WO 03/79786 (Hallahan)]. Dihydronepetalactone can be produced by contacting purified nepetalactones, or mixtures comprising various nepetalactones, with hydrogen in the presence of a catalyst, as described for example by Regnier et al [Phytochemistry (1967) 6:1281-1289]; Waller and Johnson [Proc. Oklahoma Acad. Sci. (1984) 64:49-56]; and U.S. Pat. No. 7,067,677 (Manzer).
Catmint oil, which contains a mixture of stereoisomers of nepetalactone (including trans-cis nepetalactone and cis-trans nepetalactone), can be used as a source of nepetalactone for the hydrogenation reaction described above. The hydrogenation of trans-cis nepetalactone at high temperatures may, however, lead to the formation of undesired end-products such as puleganic acid. It is thus desirable to perform the hydrogenation reaction primarily on the cis-trans isomer, and preferably on the cis-trans isomer alone.
U.S. Ser. No. 06/121,134 describes a method for the separation of ZE-nepetalactone and EZ-nepetalactone from catnip oil by dissolving the catnip oil in at least one water-immiscible, non-halogenated solvent, and mixing this solution with an aqueous solution comprising at least one inorganic base. In the presence of the aqueous base, the ZE-nepetalactone is hydrolyzed to ZE-nepetalic acid. The aqueous phase containing ZE-nepetalic acid may be separated from the organic phase containing EZ-nepetalactone. The aqueous phase, optionally, can further be acidified and added to at least one organic solvent to lactonize the ZE-nepetalic acid, in the presence for example of p-toluene sulfonic acid, to ZE-nepetalactone. Thus, this approach requires the hydrolysis of ZE-nepetalactone, and may involve the regeneration of ZE-nepetalactone from ZE-nepetalic acid.
Alternatively, Libikas et al [J. Nat. Prod. (2005) 68:886-890] used the base 1,8-diaza-bicyclo[5.4.0]undec-7-ene to convert a trans-cis nepetalactone to cis-trans nepetalactone in refluxing xylene, followed by separation using liquid chromatography. Sakan et al [Tetrahedron Letters (1965) 6:4097-4102] have also transformed trans-cis isonepetalactone to nepetalactone by heating with potassium carbonate (K2CO3) in xylene. Approaches such as the foregoing rely on the use of a solvent such as xylene.
A need thus remains for a method for converting trans-cis nepetalactone to cis-trans nepetalactone that has a minimum of steps, and eliminates steps such as the addition of a co-solvent or the use of an extraction or regeneration step.